Investigations of the pulmonary circulation in man have been among the most difficult to undertake in human physiology and pathology. They have generally required invasive methods which are not applicable to serial hemodynamic follow-up. The approach of this proposal has been to develop and apply non-invasive methods to investigate alterations of the pulmonary circulation in health and disease during physical stress and after administration of pharmacologic agents. In recent years, the keystone of our non-invasive approach has been the rebreathing technique for estimation of diffusing capacity, pulmonary capillary blood flow, tissue volume and oxygen consumption. We have been dissatisified with the reproducibility of pulmonary tissue volume measurements in man and plan to modify the method to incorporate two more additional gases, dimethyl ether and ethyl iodide. Using the bronchofiberscope we could use this method to examine lobar and segmental lung functions which might aid in the diagnosis of pulmonary emboli and preoperative assessment of bullous disease and lung cancer for resectional surgery. We have also developed non-invasive methods in clinical polysomnography which we intend to apply in monitoring of cardiopulmonary patients. Since hypoxemia provokes pulmonary hypertension, it is important to distinguish factors responsible, e.g. periodic sleep apnea, hypoventilation, oversedation, abuse of nocturnal oxygen, etc. Effects of changes in environmental temperature, humidity and pollutants and their interrelation with exercise on pulmonary circulatory parameters should establish limits to these stresses in normals and patients with cardiopulmonary disorders. In our animal laboratory, invasive studies form a basis for investigations in man. Recently we found that intravenous administration of copper sulfate in both dogs and sheep appears to produce selective pulmonary hypertension. The physiologic and histologic mechanisms for this phenomenon will be extensively investigated. In summary, the experiment in this proposal will provide basic physiologic information on the pulmonary circulation in health and disease and provide a rational approach to pulmonary hypertensive states.